A Single Missense RPGR Mutation in Families With Either Recessive or Dominant–Like X–Linked Retinitis Pigmentosa

Abstract

Abstract: : Purpose: To study retinal function and genetic etiology of disease in male and female patients from three families with X–linked retinitis pigmentosa (XLRP). Methods: Ophthalmic evaluation included a full clinical exam, perimetry, color vision testing, and full field electroretinography. Blood samples were collected from family members for nucleic acid isolation and / or karyotype analysis. The single–strand conformation polymorphism technique and direct sequencing were used to screen the patients’ DNA for mutations in the RPGR gene. The inactivation pattern of the X–chromosome in females was evaluated by the androgen–receptor method. Results: A screen for RPGR mutations in family MOL0052 from Israeli origin revealed a missense mutation, Gly275Ser, which was found to cosegregate with the disease. This mutation was previously reported in two European families. Clinical evaluation of males and females from these three distinct families revealed a clear difference in severity of disease in female carriers. Obligate carriers from the two European families (P300318 and RP300304) had no visual complaints and displayed only slightly reduced ERGs, normal to subnormal dark adaptation, and normal visual fields, while those from the Israeli family suffer from low visual acuity, severely reduced ERG amplitudes and constricted visual fields. Haplotype analysis revealed two different haplotypes: one was shared by the European patients while the other was unique to the Israeli patients. This indicates that the mutation arose twice independently and occurred on two different X–chromosome backgrounds. A series of genetic analyses including X–inactivation pattern, karyotype analysis, RPGR expression level, and mutation screening of candidate genes did not yet reveal the underlying cause for the differences in disease severity in female carriers. Conclusions: To the best of our knowledge, this is the first report of the same mutation being associated with either recessive or dominant–like X–linked disease. This leads us to predict that an additional gene (or genes) linked to RPGR probably modulates disease expression in severely affected carriers.

Keywords: retinal degenerations: hereditary • genetics